A translational approach to severe acute pancreatitis

Despite decades of research, it is still unclear why some patients with acute pancreatitis develop severe, life-threatening complications while others resolve uneventful. There are still significant knowledge barriers that prevent the successful translation of early animal studies to large-scale clinical trials. This thesis has mainly aimed to identify disease modifiers that can be targeted to prevent clinical deterioration. We hypothesized that the individual’s genetic background and the composition and function of its gut microbiota are major contributors for severe complications such as persistent (multiple) organ failure and secondary infections.
Through a comprehensive systematic review of the literature, we were able to identify credible associations between laboratory and genetic markers, and the risk and severity of acute pancreatitis. In addition, using a large cohort of patients we identified novel genetic associations in the genes ZNF106 and SLC52A1 with (early) multiple organ failure in acute pancreatitis. Finally, we were able to demonstrate that manipulation of the gut microbiota through western-type diet feeding impacted infections and mortality in animal models of necrotizing pancreatitis and postoperative abdominal sepsis. More importantly, we observed that this lethal phenotype was reversed by oral prophylactic butyrate supplementation in mice with necrotizing pancreatitis.
While these results may be used to direct future translational studies and clinical trials, we must appreciate the complexity of the interplay between host and microbial factors that underlie these severe conditions. A deep sequential analysis of these factors using advanced techniques (i.e., metagenomics, metabolomics, [epi-]genomics, transcriptomics, single-cell sequencing), clinically relevant (animal) models and large well-described patient cohorts may provide us with a more detailed understanding.